Acrocallosal syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Acrocallosal syndrome is a rare condition characterized by a brain abnormality called agenesis of the corpus callosum, the presence of extra fingers and toes (polydactyly), and distinctive facial features. The signs and symptoms of this disorder are present at birth, and their severity varies widely among affected individuals.

Agenesis of the corpus callosum occurs when the tissue that connects the left and right halves of the brain (the corpus callosum) fails to form normally during the early stages of development before birth. Other brain abnormalities, including the growth of large cysts in brain tissue, have also been reported in people with acrocallosal syndrome. The changes in brain structure associated with this condition lead to delayed development and intellectual disability, which is most often moderate to severe. Some affected individuals also experience seizures.

Extra fingers and toes are common in people with acrocallosal syndrome. The extra digits can be on the same side of the hand or foot as the pinky or little toe (postaxial polydactyly) or on the same side as the thumb or great toe (preaxial polydactyly). Some affected individuals also have webbed or fused skin between the fingers or toes (syndactyly).

Distinctive facial features that can occur with acrocallosal syndrome include widely spaced eyes (hypertelorism) and a high, prominent forehead. Many affected individuals also have an unusually large head size (macrocephaly).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the KIF7 gene have been found to cause acrocallosal syndrome. Mutations in another gene, GLI3, can also cause features of this disorder. However, the signs and symptoms overlap significantly with those of a similar disorder called Greig cephalopolysyndactyly syndrome (which is also caused by GLI3 gene mutations), so acrocallosal syndrome resulting from GLI3 gene mutations is sometimes considered a severe form of that condition.

The proteins produced from the KIF7 and GLI3 genes play critical roles in the normal shaping (patterning) of many tissues and organs before birth. The proteins are part of a chemical signaling pathway called Sonic Hedgehog signaling. This pathway is involved in cell growth, cell specialization, and the patterning of structures such as the brain and limbs.

Mutations in either the KIF7 or GLI3 gene are thought to impair Sonic Hedgehog signaling, which has wide-ranging effects on development before birth. The roles of these genes in brain and limb patterning may help explain why mutations lead to agenesis of the corpus callosum, polydactyly, and the other features of acrocallosal syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

When acrocallosal syndrome is caused by KIF7 gene mutations, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Acrocallosal syndrome (or severe Greig cephalopolysyndactyly syndrome) resulting from GLI3 gene mutations is considered autosomal dominant , which means one copy of the altered gene in each cell is sufficient to cause the disorder. This condition results from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

This condition appears to be rare. Only a few dozen cases have been reported in the medical literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Aplasia/Hypoplasia of the corpus callosum · Very frequent (99-80%)

Absence or underdevelopment of the corpus callosum.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Intellectual disability, severe · Very frequent (99-80%)

Severe intellectual disability (ID) is defined as a type of ID characterized by severely sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 20-34.

Macrocephaly · Very frequent (99-80%)

Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.

Postaxial hand polydactyly · Very frequent (99-80%)

Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).

Dandy-Walker malformation · Frequent (79-30%)

A congenital brain malformation typically characterized by incomplete formation of the cerebellar vermis, dilation of the fourth ventricle, and enlargement of the posterior fossa. In layman's terms, Dandy Walker malformation is a cyst in the cerebellum (typically symmetrical) that is involved with the fourth ventricle. This may interfere with the ability to drain cerebrospinal fluid from the brain, resulting in hydrocephalus. Dandy Walker cysts are formed during early embryonic development, while the brain forms. The cyst in the cerebellum typically has several blood vessels running through it connecting to the brain, thereby prohibiting surgical removal.

Prominent occiput · Frequent (79-30%)

Increased convexity of the occiput (posterior part of the skull).

Sloping forehead · Frequent (79-30%)

Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.

Other findings in the same source

From: Orphanet

Additional reported features include Triphalangeal thumb (Frequent (79-30%)); Abnormality of the clavicle (Occasional (29-5%)); Congenital diaphragmatic hernia (Occasional (29-5%)); Cryptorchidism (Occasional (29-5%)); Hypospadias (Occasional (29-5%)); Inguinal hernia (Occasional (29-5%)); Sensorineural hearing impairment (Occasional (29-5%)); Tall stature (Occasional (29-5%)); Wide anterior fontanel (Occasional (29-5%)); Aplasia/Hypoplasia of the cerebellum (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Acrocallosal syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Acrocallosal syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.